The primary objective of this research is to characterize the mode by which certain drugs (with the potential to interact with DNA) activate genes. We have defined and utilized an assay which rapidly and accurately selects compounds capable of activating the genes responsible for isoflavonoid (pisatin) production (1-19) in Pisum sativum. A second assay measures the synthesis of phenylalanine ammonia lyase (PAL), an enzyme in the biosynthetic pathway of pisatin. The activation of the genes involved is dependent on newly-synthesized RNA which we now know represents the poly A containing messenger RNA (19). We have previously shown that these pisatin inducing compounds penetrate the cells, accumulate in the nuclei of higher organisms, and promote characteristic changes in the template activity, dye binding potential, and ultrastructural features in chromatin. The induction potential appears to relate to the drugs' potential to interact with DNA. We have identified many of the reactive groups involved in induction. These reactive groups along with their proper steric spacings are found in drugs with widely varying medical applications--e.g. antidepressants, antihistamines, tranquilizers, antitumor, antimalarial. Some of these drugs reportedly (a) intercalate between DNA base pairs (20), (b) alkylate or substitute for moieties in double-stranded DNA (21, 22), or (c) are polyamines or basic compounds which are capable of ionic binding to the phosphate groups in DNA (23). Six inducer compounds have been synthesized or purchased as radioisotopes and will be utilized to monitor cellular uptake and localization in chromatin and other cell components. The effects of inducers on chromatin will be evaluated from electron micrographs, template assays (24), and density gradient fractionations (25, 26). Also various physical-chemical mesurements such as melting temperature curves and dye binding potential will be utilized in evaluating conformational changes in the chromatin fractions extracted from induced and non-induced tissues. Corresponding changes in mRNA and protein synthesis patterns in the intact cell will also be monitored.